Repetitive natriuresis and blood pressure. Long-term calcium entry blockade with isradipine.

Abstract

SUMMARY The long-term effects (3.5 months) of a new calcium entry blocker of the 1-4-dihydropyridine class, isradipine , on renal hemodynamics and excretional parameters were investigated in 10 essential hypertensive subjects (World Health Organization Classes I and II). Blood pressure and renal vascular resistance fell significantly (p < 0.001), and a slight increase in glomerular filtration rate and renal plasma flow was seen (p<0.05). Output of fluid from the proximal tubules, measured as clearance of lithium and uric acid, increased significantly (p<0.01 and p<0.05, respectively), and a compensatory increase in absolute reabsorption of sodium beyond the proximal tubular level accompanied by an increase in clearance of potassium was noted. A 40% increase in the resultant clearance of sodium (p<0.01) and an increase in diuresis (p<0.05) followed the morning dose of isradipine after 3.5 months of treatment. Changes in blood pressure were significantly correlated with changes in absolute proximal reabsorption of sodium (r = 0.81), excretion of sodium (r = -0.64), and diuresis (r = -0.80). Thus, the natriuretic properties of calcium entry blockers may be more important for the long-term antihypertensive effect than the vasodilator effect per se. A model for renal sodium handling following treatment with calcium entry blockers was proposed. Although a causal relationship is not implied, isradipine induced a sustained, repetitive postdose effect on proximal fluid output, net natriuresis, and diuresis, that was intimately related to the long-term blood pressureregulating response.

Renal effects of the new calcium channel blocking drug isradipine

“…The present results demonstrate an increase in sodium excretion 1 to 3 h after oral administration of 5 mg isradipine in normotensive subjects, and an increase of urine volume after i to 2 h. The results are in accordance with other studies, in which increases in sodium excretion [6,7,9] and urine volume [6,9] were seen in essential hypertensive patients, but they are not fully in agreement with reports in which increases in sodium excretion [8] and urine volume [7,8] did not reach statistical significance.…”

“…GFR (except for a transient decrease in the first h after drug intake), RPF, RVR and FF remained unchanged throughout the 5 h of observation in accordance with some findings in hypertensive patients (GFR [7][8][9], RPF [7,9], FF [6,7]), but in contrast to others (increase of RPF [6,8], GFR [6]; decrease of FF [8], RVR [6]). In hypertensive patients RVR was decreased and PRF was increased after 20 mg nifedipine, whereas no effect was shown in normotensive patients [13].…”

“…The oral administration of 5 mg isradipine had no significant effect on blood pressure or heart rate in healthy, normotensive controls, whereas SBP and DBP were significantly howered by it in essential hypertensive patients [6--9], and heart rate was either unchanged [7,8] or increased [6,9]. Lederballe Pedersen et al [10] did not find a fall in blood pressure in normotensive controls after administration of nifedipine, despite a marked effect in hypertensive patients.…”

“…This does not support a dominant proximal tubular natriuretic effect, as the mechanism of the isradipine-induced natriuresis. In contrast to these resuits, Krusell et al [6] and Pedersen et al [7] demonstrated an increase in uric acid clearance in hypertensive patients after isradipine administration, suggesting a proximal tubular mechanism. In addition, the increase in lithium clearance [6] after isradipine treatment is thought to be a measure of increased proximal fluid output.…”

“…A smaller negative inotropic effect and less reflex tachycardia compared to nifedipine make isradipine a promising compound in the treatment of patients with coronary artery disease and congestive heart failure [5]. Krusell et al [6] demonstrated an increase in GFR, RPF, sodium clearance, and lithium clearance, and a decrease in renal vascular resistance in essential hypertensive patients after 3.5 months of treatment with 17.5 mg. d-1 isradipine. However, after 2 years of isradipine treatment (13.3 mg-d-1) GFR and RPF were no longer significantly increased; data for lithium clearance and renal vascular resistance were not given [7].…”